Intermittent fasting preserves beta-cell mass in obesity-induced diabetes via the autophagy-lysosome pathway

Haiyan Liu, Ali Javaheri, Rebecca J. Godar, John Murphy, Xiucui Ma, Nidhi Rohatgi, Jana Mahadevan, Krzysztof Hyrc, Paul Saftig, Connie Marshall, Michael L. McDaniel, Maria S. Remedi, Babak Razani, Fumihiko Urano, Abhinav Diwan

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Obesity-induced diabetes is characterized by hyperglycemia, insulin resistance, and progressive beta cell failure. In islets of mice with obesity-induced diabetes, we observe increased beta cell death and impaired autophagic flux. We hypothesized that intermittent fasting, a clinically sustainable therapeutic strategy, stimulates autophagic flux to ameliorate obesity-induced diabetes. Our data show that despite continued high-fat intake, intermittent fasting restores autophagic flux in islets and improves glucose tolerance by enhancing glucose-stimulated insulin secretion, beta cell survival, and nuclear expression of NEUROG3, a marker of pancreatic regeneration. In contrast, intermittent fasting does not rescue beta-cell death or induce NEUROG3 expression in obese mice with lysosomal dysfunction secondary to deficiency of the lysosomal membrane protein, LAMP2 or haplo-insufficiency of BECN1/Beclin 1, a protein critical for autophagosome formation. Moreover, intermittent fasting is sufficient to provoke beta cell death in nonobese lamp2 null mice, attesting to a critical role for lysosome function in beta cell homeostasis under fasting conditions. Beta cells in intermittently-fasted LAMP2- or BECN1-deficient mice exhibit markers of autophagic failure with accumulation of damaged mitochondria and upregulation of oxidative stress. Thus, intermittent fasting preserves organelle quality via the autophagy-lysosome pathway to enhance beta cell survival and stimulates markers of regeneration in obesity-induced diabetes.

Original languageEnglish
Pages (from-to)1952-1968
Number of pages17
JournalAutophagy
Volume13
Issue number11
DOIs
StatePublished - Nov 2 2017

Keywords

  • autophagy
  • beta cells
  • diabetes
  • intermittent fasting
  • lysosomes

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